Process for manufacturing 3-hydroxy-3-Methylbutanoic acid

ABSTRACT

A method for manufacturing 3-hydroxy-3-methylbutanoic acid (HMB) in commercially viable amounts is disclosed. The reaction mixture cycles through an external heat exchanger while the primary reactant is added in a warmer so as to control and maintain a low temperature for the reaction mixture. The manufacturing process herein disclosed increases yield while decreasing reaction time from the synthetic processes currently practiced.

This is a continuation of U.S. patent application Ser. No. 08/685,599,filed Jul. 19, 1996, which is incorporated herein by reference.

FIELD OF INVENTION

This invention relates to methods for manufacturing3-hydroxy-3-methylbutanoic acid (HMB) in high yield, in large batchamounts, with high quality, and in a relatively short amount of time.

BACKGROUND OF INVENTION

Several reports have recently appeared disclosing that HMB exhibitssignificant efficacy for nitrogen retention and muscle building inhumans. See Nissen et al., U.S. Pat. No. 5,348,979; Phillips, MuscleMedia 2000 (October 1995), “HMB New Drug-Free Mass Builder;” these andall other references cited herein are expressly incorporated byreference as if fully set forth in their entirety herein. Promotingnitrogen retention has therapeutic importance for trauma patients andfor patients showing loss of protein due to stress conditions. Moreover,administration of HMB has been reported to enhance the immune responseof mammals (Nissen et al., U.S. Pat. No. 4,992,470), and to increaselean tissue development in meat-producing animals (Nissen et al., U.S.Pat. Nos. 5,087,472 and 5,028,440).

The structure of HMB is reproduced below.

Despite these several reports on the beneficial properties of HMB, thissubstance is currently available only in small quantities due to thelack of a suitable synthetic procedure for commercial production of HMB.In fact, during recent years, several chemical manufacturing companieshave sought to develop a high output synthetic process for HMB. Theseattempts have been based on the reactions described in Coffinan et al.,Journal of the American Chemical Society 80:2882-2887 (1958); Wagner &Zook, Synthetic Organic Chemistry 422-423, 458 (1953); March, AdvancedOrganic Chemistry, Rxn. 2-43, 567 (3d ed. 1985); Blatt, OrganicSynthesis 2:428429, 526-527 (1943); Blatt, Organic Synthesis 3:302-303(1955) Blatt, Organic Synthesis 5:8-9 (1973). According to thisprocedure, diacetone alcohol (DIA) is subjected to alkaline sodiumhypochlorite oxidation to produce HMB.

In a previous attempt at producing a commercially viable procedure, anaverage yield of 0.26 pounds of HMB per pound of DIA was achieved, withthe most efficient batch achieving a yield of 0.325 pounds of HMB perpound of DIA. The reaction was typically run in a reactor no greaterthan 200 gallons, with an average charge of 156 gallon of bleach andabout 95 pounds of DIA, to produce about 25 pounds HMB per batch. Thisprocess was plagued by an inability to control reaction temperature, andthis inability mandated the use of small batch sizes. This processmoreover failed to provide access to HMB in quantities sufficient toenable therapy on humans or animals. Thus, a need exists for an HMBmanufacturing process that will allow production of high quantities ofhigh quality HMB, and will permit HMB manufacture on a large scale, hasbeen achieved through the improvements described herein.

SUMMARY OF THE INVENTION

This invention is based on the unexpected discovery that, in a largescale process for production of HMB using a main reaction tank foroxidation of an HMB precursor, the batch size, yield, and quality ofproduct can be dramatically increased by use of an external heatexchanger with constant flow loop to maintain a reaction temperature ofbelow 15° C. The apparatus of the invention includes a reaction tankhaving a first temperature probe within the reaction tank, and anassociated reaction mixture recycling cooling loop. The cooling loopincludes an outlet passage from the reaction tank in fluid communicationwith an external heat exchanger, and further includes an inlet passagewhich connects the external heat exchanger to the reaction tank. Thissystem allows the reaction mixture to flow from the reaction tankthrough the outlet passage to the heat exchanger, and then through theinlet passage back to the reaction tank. A second temperature probe istypically provided on the outlet passage. The external heat exchangermay include a cooling inlet pipe and a cooling outlet pipe whichconnects the external heat exchanger to an auxiliary chiller. One ormore additional temperature probes may be included on the cooling inletpipe, cooling outlet pipe, or both. Moreover, the inlet passage, whichprovides flow of reactant from the external heat exchanger back to thereaction tank, may be equipped with a further temperature probe.

The chemical process of the invention provides a method to produce HMBfrom 4-hydroxy-4-methyl-2-pentanone (diacetone alcohol, or DIA).According to the method of the invention, the reaction tank is chargedwith a solution of oxidant, preferably hypochlorite, hypobromite, orhypoiodite. The reaction tank and external heat exchanger are thenoperated in order to cool the solution to a temperature below 15° C.,more preferably below 12° C., more preferably below 10° C., morepreferably below 8° C., more preferably below 6° C., and most preferablybelow 5° C. Once the appropriate temperature has been achieved asindicated by one or more of the temperature probes, DIA is fed into thereaction tank while maintaining the solution at a temperature of 15° C.or below. During this step, it is important to carefully monitor thetemperature, and to regulate the rate of addition of DIA so that thetemperature does not rise above 15° C. The oxidation of DIA is anexothermic reaction, and therefore uncontrolled addition of DIA willcause a rise in temperature of the reaction mixture. If the reactiontemperature is allowed to rise above 15° C., byproducts which mayinclude acetic acid and/or diol will be formed, and this side reactionwill, of course, reduce the yield and amount of the desired product HMB.We have observed that at −10° C. the ratio of HMB to diol byproduct is5.9:1, while at 5° C. the ratio is 5.0-5.3:1, whereas when thetemperature is uncontrolled, the ratio becomes 2:1. After the reactionof DIA is complete, the reaction tank is either acidified to produce HMBor treated with a salt to produce a salt thereof.

In accordance with the method herein disclosed, we have been able toachieve an average yield of 0.44 pounds of HMB per pound of DIA, asignificant and unexpected 70% improvement over the earlier usedprocess. The highest batch yield with our procedure has been 0.50 poundsof HMB per pound of DIA. Not only has yield improved, but addition ofDIA can be conducted at a rate 10-20 times faster than the rate used inthe earlier process. In the improvement described herein, more than tentimes as much DIA was added in a 4- to 8-hour period as was added in an8-hour period during the earlier process. This improvement in thereactant addition rate is also significant and unexpected.

In a preferred embodiment, the reaction tank is charged withhydrochloric acid after the reaction of DIA is completed, and the pH isadjusted to approximately 3.5 or lower. Thereafter, HMB is extractedwith an organic solvent, and the organic solvent may be removed byvacuum distillation in order to concentrate HMB. In certain embodiments,the extraction solvent is ethyl acetate. In another embodiment, the heatexchanger is a carbate heat exchanger, and includes a cooling tankholding a cooling fluid, a cooling inlet passage, and a cooling outletpassage, all in fluid communication with the external heat exchanger.The cooling fluid can be a solution of methanol and water, and thecooling tank is optimally maintained at a temperature of lower than −10°C., more preferably lower than −20° C. Thus, according to the HMBmanufacturing process disclosed herein, the reaction mixture may bepumped through the external heat exchanger at a rate of at least 80gallons/minute, more preferably 90 gallons/minute, more preferably 100gallons/minute, more preferably 110 gallons/minute or more. Duringcharging of the tank with DIA, the rate of addition of DIA may beadjusted based on temperature readings at the first and secondtemperature probes, which refer to the temperature probe within thereaction tank and the temperature probe on the outlet passage.

In another embodiment, the reaction tank is equipped with an adjustabledecant tube to facilitate rapid extraction of organic solvent. Theadjustable decant tube includes an elongated tubular member whichextends through an opening at the top of the reaction tank and down intothe reaction tank, terminating in a “J” section which allows a cleandecant of organic solvent. The decant tube includes, at its top portion,an attachment which allows connection of the tube to a pulley systemwhich is used to raise and lower the adjustable decant tube within thereaction tank as described below in more detail.

BRIEF DESCRIPTION OF DRAWINGS

Reference is next made to a brief description of the drawings, which areintended to illustrate the processing apparatus for use in the methoddisclosed herein. The drawings and detailed descriptions which followare intended to be merely illustrative and are not intended to limit thescope of the invention as set forth in the appended claims.

FIG. 1 is a diagram showing a reaction tank and external heat exchangerfor use in a process of manufacturing HMB. This embodiment shows thedecant tube containing a “J” section and hook for connection to a pulleysystem.

FIG. 2 is a diagram showing the process system used for the productionof HMB crude oil.

FIG. 3 is a diagram showing the process system used for the productionof finished HMB from the HMB crude oil.

DETAILED DESCRIPTION

We have discovered that maintaining low temperatures during theproduction of 3-hydroxy-3-methylbutanoic acid (HMB) is an importantfeature of the HMB manufacturing process owing to the exothermic natureof the reaction. Methods of synthesizing HMB to date have beeninsufficient for producing commercially viable amounts of HMB. However,the introduction of an external heat exchanger to the process, alongwith the innovative injection of the primary reactant and the constantmeasuring of the reaction mixture temperature, allows for a significantincrease in the reaction time and yield of HMB.

A reaction system having a recycling cooling loop as used herein isdepicted in FIG. 1. The reaction mixture recycling cooling loop system50 is responsible for controlling the temperature of the reactionmixture, and constitutes a substantial improvement for the systemdisclosed herein. The system is comprised of reactor 1, typically aglass-lined reactor selected to have a volume that will accommodate thequantity of reactants to be added, generally a volume of greater than200 gallons, more preferably greater than 400 gallons, more preferablygreater than 800 gallons, more preferably greater than 1,000 gallons,more preferably greater than 1,200 gallons, and for a typical batch,1,500 gallons or more. The system also includes an external heatexchanger 17, more preferably a carbate heat exchanger, used to cool thereaction mixture. The reactor 1 is surrounded by cooling jacket 2 whichhas at least one cooling solution inlet 3, and possibly additionalinlets 4 and 5, and a cooling solution outlet 6 to allow coolingsolution to fill cooling jacket 2 and surround reactor 1. The reactor 1also contains an agitator 8 for the purpose of mixing the contents ofreactor 1. A temperature probe 9 extends into reactor 1, preferably fromthe top, to provide means for monitoring the temperature of the contentsof reactor 1.

The reactor 1 will generally have a capacity of greater than 200gallons, more typically greater than 300 gallons, more typically greaterthan 600 gallons, more typically greater than 1,000 gallons, moretypically greater than 1,300 gallons, and generally 1,500 gallons ormore. It will be understood that the use of a large reactor is notmerely a matter of routine design selection, but is a crucial parameterfor scale-up of the HMB reaction which is enabled only by use of thecooling technology which we have developed. Thus, by using previouscooling techniques, it was not possible to scale-up to large sizereaction equipment as we have now disclosed. Instead, previous work inthis area was limited to use of small size reactors of about 200 gallonsor less because previous researchers were not able to control reactiontemperatures using large scale equipment and the corresponding largerscale of reactants, as we now disclose.

Outlet passage 11 allows fluid to flow from reactor 1 to heat exchanger17. A bottom valve 10 controls the flow of contents out of reactor 1.The outlet passage 11 passes through bottom valve 10 and connects to aTeflon® butterfly valve 12, which allows the drained contents to flowinto a glass spool piece 14 providing visualization of the materialflowing through outlet passage 11. Immediately downstream of glass spoolpiece 14 is situated inlet passage 41, which branches into passages 42and 43. Passage 42 allows for the addition of nitrogen gas for flushingthe reaction mixture recycling cooling loop. Addition of nitrogen gasthrough passage 42 is controlled by valve 44. Passage 43 allows for theremoval of chloroform from reactor 1 and for the addition of acid to thereaction mixture recycling cooling loop. The removal of chloroform andthe addition of acid is controlled by valve 45 situated on passage 43.Butterfly valve 13 is situated further downstream of inlet passage 41along outlet passage 11.

Continuing further along outlet passage 11, inlet passage 37 allowsaddition of DIA as controlled by valve 38. After the juncture with inletpassage 37, outlet passage 11 passes through flex joint 36 and intocentrifugal pump 15. Outlet passage 11 continues beyond centrifugal pump15 and attaches to external heat exchanger 17. A temperature probe 16 isattached to outlet passage 11 downstream of centrifugal pump 15 andprior to the junction of outlet passage 11 with heat exchanger 17.

The external heat exchanger 17 includes inlet passage 18 to allow theflow of cooling solution from the auxiliary chiller system describedbelow. Heat exchanger 17 also includes outlet passage 19 to allow theflow of cooling solution back to the auxiliary chiller system. Atemperature probe 20 may be attached to inlet passage 18 adjacent toheat exchanger 17, and temperature probe 21 may be attached to outletpassage 19 adjacent to heat exchanger 17.

An inlet passage 22 completes the flow of material through the reactionmixture recycling cooling loop by providing fluid communication fromheat exchanger 17 to reactor 1. A temperature probe 23 may be mounted oninlet passage 22 adjacent to heat exchanger 17 for the purpose ofmeasuring the temperature of the reaction mixture as it exits heatexchanger 17.

A complete diagram of an HMB crude flow system is depicted in FIG. 2.Referring to FIG. 2, the auxiliary chiller system includes chiller holdtank 107 and auxiliary chiller 108. The chiller hold tank 107 providescooling solution to external heat exchanger 17 through inlet passage 18and to the cooling jacket 2 surrounding reactor 1 through one or more ofcooling solution inlets 3, 4, and 5 (shown in FIG. 1), which branch offfrom inlet passage 18. Pump 7, situated along inlet passage 18, forcescooling solution through the cooling solution loop. Pump 7A (shown inFIG. 1) is also situated along inlet passage 18, immediately upstream ofcooling solution inlets 3, 4, and 5, for the purpose of providing aboost to the rate of cooling solution flow, if desirable. Coolingsolution returns to chiller hold tank 107 through outlet passage 19 fromthe external heat exchanger 17, which is joined by outlet passage 6 fromcooling jacket 2. Passage 109 allows the transfer of cooling solutionbetween chiller hold tank 107 and auxiliary chiller 108. A pump 110situated along passage 109 transfers cooling solution between chillerhold tank 107 and auxiliary chiller 108.

The auxiliary chiller 108, chiller pump 110, and an associated generator(not shown) are turned on prior to the addition of oxidant to reactor 1in order to pre-chill the cooling solution. The chiller maintains thetemperature of the cooling solution in the chiller hold tank 107 at asufficiently low temperature to maintain the reaction mixture at anappropriate temperature. The cooling solution is thus generallymaintained at between −10 to −20° C. The cooling solution typicallycomprises a methanol/water mixture, more preferably ⅓ methanol and ⅔water, more preferably 1,000 gallons of water and 632 gallons ofmethanol. In the preferred embodiment, the specific gravity of thecooling solution will generally be approximately 0.95, more preferably0.9531 (30% methanol) or lower.

In use, a process of synthesizing crude HMB begins by charging thereactor 1 with a quantity of oxidant, e.g., sodium hypochlorite, sodiumhypobromite, sodium hypoiodite, calcium hypochlorite, calciumhypobromite, or calcium hypoiodite. Where sodium hypochlorite is used,12.5-15% (pH 12.0-13.5), more preferably 14.5%, sodium hypochlorite fromthe glass-lined oxidant bulk storage container 111 is passed throughpassage 113, which preferably is a dedicated plastic line. The quantityof oxidant charged into reactor 1 is preferably greater than 200gallons, more preferably greater than 400 gallons, more preferablygreater than 800 gallons, most preferably greater than or equal to 1,200gallons. The flow of oxidant from bulk storage container 111 iscontrolled by valve 114 and pump 115, which is preferably an air drivenplastic pump, both of which are situated along passage 113 in closeproximity to bulk storage container 111. The bulk storage container 111is filled from an external delivery source through inlet passage 112.

Referring again to reactor 1 and its associated external heat exchanger,agitator 8 and then pump 7 are turned on to circulate cooling solutionthrough external heat exchanger 17 and cooling jacket 2. Pump 15 is thenused to circulate the contents of reaction tank 1 through external heatexchanger 17, once valves 10, 12, and 13 are opened, and valves 38, 44,45, and 118 are closed. The temperature of the oxidant is lowered to0-5° C. by heat exchange which occurs both through the cooling jacketand the external heat exchanger. The temperature of the contents of theglass-lined reactor 1 is controlled through a combination ofmanipulating chiller recirculation tank flow (throttling the tank outletvalve), shutting on and off the chiller cooling loop pump 7, andadjusting booster pump 7A (shown in FIG. 1) to increase or decrease therate of flow through the cooling loop. The chiller unit pump 110generally remains on constantly.

Once the oxidant within reactor 1 has been chilled to below 10° C.,preferably 0-5° C., the inlet temperature at temperature probe 16, andoptimally, the outlet temperature at temperature probe 23, are noted.Next, diacetone alcohol, the precursor of HMB, is added to the reactionmixture recycling cooling loop from the DIA storage container 104,through inlet passage 37, passing through feed pump 102, preferably aTeflon® feed pump, and check valve 38, both of which are connected toinlet passage 37. DIA is added over a 4- to 8-hour period at a rate ofapproximately 0-5 pounds per minute, preferably 2.5 pounds per minute.The total amount of DIA added for one batch is typically 100 or morepounds, more preferably 300 or more pounds, more preferably 500 or morepounds, more preferably 700 or more pounds, more preferably 900 or morepounds, with an average of about 957 pounds. It will be understood thatthe quantity of DIA added will depend on the quantity of bleach chargedto the reactor, and will typically have a ratio of about 1:12 by weight(DIA:oxidant), presuming an oxidant concentration of 12.5-15%. Thisratio can also be expressed as about 1:1.2 pounds DIA to gallons ofoxidant. By comparison to known techniques, DIA addition couldpreviously be added at no more than 95 pounds over a period of 8 hours.The temperature probes 9 and 16, and preferably at least one additionalprobe selected from probes 20, 21, and 23, are monitored to determinehow to set the rate of addition of DIA to maintain the temperature atinlet passage temperature probe 16 below 10° C., preferably between 0-5°C.

With the start of DIA addition, full cooling is in place and temperatureadjustments are performed by any one of a combination of adjusting therate of DIA addition, adjusting the rate of flow of cooling solutionthrough the cooling loop, increasing the flow rate of the reactionmixture in the reaction mixture recycling cooling loop by adjusting pump15, and adjusting the temperature of cooling solution in the coolingloop. In a preferred embodiment, temperature adjustments are performedsolely by adjusting the rate of DIA addition. The preferred rate of DIAaddition is 0-5 pounds per minute. The exotherm produced by the reactionis virtually nonexistent over the addition of the last 10% of the DIA.Therefore, the auxiliary chiller flow rate will have to be adjusted bythrottling the outlet valve (not shown) for chiller hold tank 107 orshutting off the chiller cooling loop pump 7 entirely.

After DIA addition is completed, the DIA line is flushed with water. Thetemperature of reactor 1 is then maintained at about 3-10° C. Carbonmonoxide forms in reactor 1 at this time, so that the reactor containervent (not shown) should be fully open and the manway 24 should be fullyclosed.

Acid (preferably hydrochloric acid; more preferably 1,700-2,120 poundsof 32% hydrochloric acid) is added to the reaction mixture from acidstorage container 106 through passage 43 and through inlet passage 41,passing through feed pump 103 and check valve 45. During the acidaddition, the reaction mixture recycling cooling loop continues tooperate in order to provide good mixing. In one embodiment, the acid isadded and the temperature is maintained at approximately 10-20° C. ThepH of the reaction mixture is monitored at the recycling loop samplenozzle 40 to insure that the pH is maintained at about between 3.0-3.5,preferably 3.0-3.2. The reaction mixture is maintained at 10-20° C. forabout two hours.

Further, hydrochloric acid is added in the same manner as describedabove, frequently checking pH and stopping between about pH 3.0 and 3.2.The reaction mixture is agitated and recycled through the reactionmixture recycling cooling loop for 10-15 minutes, and a final pH checkis performed to ensure that the pH is between about 3.0 and 3.2 withoutdropping below about 3.0.

Bottom valve 10 is closed, and water is added to outlet passage 11 inorder to flush the reaction mixture recycling cooling loop into reactor1, and the loop is purged with a nitrogen flush added through passage 42and inlet passage 41 as regulated by valve 44. After the reactionmixture recycling cooling loop is purged, valves 10, 12, and 13 areadjusted to close off the cooling loop, and any cooling is shut off.

Agitator 8 is rested, and the reaction mixture is allowed to settle. Ahaloform layer will form as a bottom layer in reactor 1. This bottomhaloform layer is drained through outlet passage 11 by opening valves10, 12, and 45, closing valve 13, and draining through passages 41 and43.

In a preferred embodiment of the procedure, it is then desirable tostrip water from reactor 1. First, a vacuum is pulled on the reactorcontainer by applying vacuum to the receiver water strip holding tank126. Approximately one-half of the contents in reactor 1 is distilledthrough outlet means 122 and outlet passage 123 into condenser 124 andcontinuing through outlet passage 123 into water strip holding tank 126.A portion of the distilled water strip is drummed into tote 150 (severalof which may be required) at least once during the distillation sincethe distillation will remove many gallons of water strip, consistingprimarily of water but also including varying amounts of acetic acid,acetone, and possibly haloform. Once distillation is completed, thevacuum on the reactor 1 should be broken with nitrogen from nitrogeninlet 180.

Subsequent to the water strip step, the contents of reactor 1 are cooledto 25° C. with agitation, creating a thick salt slurry of product. Next,hydrochloric acid is added through the top of reactor 1 to perform afinal pH adjustment to about 3.0-3.2. The product mixture is mixed withagitator 8 for 10-30 minutes after the final pH adjustment to ensure themaintenance of the pH at about 3.0-3.2.

The product is then extracted from the salt slurry with organic solvent,preferably a polar organic solvent that is not miscible with water, mostpreferably ethyl acetate. Agitator 8 is shut off and decant tube 25 islowered to the level of the liquid. A mark is made in relation to thedecant tube 25 so that the decant tube 25 can be returned to the sameposition once the product has been extracted into the organic solvent.All lines, including passages 135, 142, and 147, which will containorganic solvent are grounded and purged with nitrogen. Organic solventis added to reactor 1 from organic solvent recovery tank 144 throughinlet passage 147, discharging from the recovery tank 144 and leadingthrough valve 148 and pump 149 and eventually into reactor 1, or from asource of fresh organic solvent 152 through an inlet means 153 into theinlet passage 147 leading to reactor 1. The decant tube 25 is raisedabove the liquid level and agitator 8 is activated. Agitator 8 is thenturned off and the contents of reactor 1 allowed to settle. The decanttube 25 is then lowered to the interface between the organic and aqueouslayers. Pump 181 is turned on, valves 182 and 184 are closed, valves 183and 185 are opened, and organic solvent is decanted to organic solventextraction tank 136 from the decant tube 25 through dip tube sightingglass 35, flexible hose 134, and outlet passage 135.

The organic solvent extraction may be performed one, two or several moretimes, checking the pH before each extraction. A pH adjustment may beappropriate and may be performed by adding acid through the top of thereactor 1 since the pH usually rises as the result of an extraction.After the extraction procedure has been completed, reactor 1 containssalt waste which is redissolved by adding into reactor 1 the waterdistilled in the earlier water strip step from the water strip holdingtank 126. The mixture of the water and salt waste is stirred withagitator 8 to ensure that all salt is in solution. The mixture is thenheated if all salt does not go into solution immediately, and water maybe added. After the salt waste has been brought into aqueous solution,the contents are heated to about 60° C. under full vacuum to remove anyresidual organics. The contents of reactor 1 are then cooled to about25° C. and pumped out by opening bottom valve 10 and valve 118, allowingthe salt solution to flow through passage 117 into the waste tank 116.Waste salt solution gathered in waste tank 116 is periodicallytransferred to bulk waste haulers through outlet means 119 by openingvalve 120.

Now that the HMB product is in solution with organic solvent inextraction tank 136, a cut is made in extraction tank 136 by openingvalve 139 and allowing any water layer which was inadvertentlytransferred to extraction tank 136 to flow from the tank through outletpassage 140. Next, extraction tank 136 and recovery tank 144 are rununder vacuum to recover the organic solvent. During this step, organicsolvent from extraction tank 136 will distill through outlet means 141into condenser 143, and continuing through outlet passage 142, intorecovery tank 144. After this preliminary distillation of organicsolvent, approximately 450-500 pounds, or approximately 40-50 gallons,of HMB crude oil will remain in extraction tank 136. This HMB crude oilis thereafter transferred to one or more product tote bins 151 byopening valve 139 and allowing the crude oil to flow from extractiontank 136 through outlet passage 140.

After the preliminary organic solvent extraction has been completed, thefinished process phase begins. Several batches of HMB crude oil arecharged into reactor 1 from tote bins 151 through bag filter 201 asillustrated in FIG. 3 to remove small amounts of residual salt. Reactor1 is heated under full vacuum to about 60-70° C. to distill residualorganic solvent into water strip holding tank 126. Once the organicsolvent take-off approaches zero, a nitrogen sparge is performed throughbottom valve 10 to sweep residual organic solvent from the crude. Asample is collected from the contents remaining in reactor 1 to checkfor organic solvent by high performance liquid chromatography analysis.

Once the product has been approved as free of organic solvent, HMB crudeoil is removed from reactor 1 and transferred into a clean tote bin 221.After obtaining a net weight of the unfinished product, a quantity ofthe unfinished product is collected to be used later in the finishingprocess for pH adjustment, if necessary. Thereafter, 5,000-9,000 poundsof ethanol or toluene, preferably ethanol, are transferred from drums oran ethanol/toluene recovery tank (not shown) into reaction tank 144 viaclean pump or vacuum. Agitator 145 is used to stir the ethanol, ensuringthat the system is fully grounded from drum through connection. Theethanol is heated to about 20° C. If the ethanol that is being used isfresh ethanol, as opposed to recovered ethanol, then water is added torecovery tank 144, according to the formula wherein the pounds of waterto be added is determined by multiplying the pounds of ethanol by 0.063.If the ethanol being used is recovered ethanol, this water may not beadded.

The unfnished/crude HMB product is transferred to recovery tank 144 fromtote bin 221 through filter 203. Recovery tank 144 is heated to about30° C. Thereafter, 500-800 pounds, preferably 50 pounds at a time, ofcalcium hydroxide, calcium oxide, calcium carbonate, or calcium acetate,more preferably calcium hydroxide USP, is added to recovery tank 144 ata controlled rate and under cooling to keep the temperature of thecontents between about 30-45° C., more preferably 40-45° C. Thetemperature of about 40-45° C. is desirable since the mixture gels below30° C. Maintaining the temperature at 45° C. will likely require addingchilled water in the cooling jacket (not shown) surrounding recoverytank 144 as needed.

The pH is adjusted to about 6.5-7.0 using the calcium hydroxide. The pHincreases quickly during this adjustment, so caution must be taken inapproaching a pH of 6.5-7.0. If the pH goal is surpassed, the HMB crudesaved from earlier in the process may be used to adjust the pH downwardinto the desired range. Once the pH adjustment is completed, therecovery tank 144 is fully purged and the temperature maintained at 45°C.

In the meantime, extraction tank 136 is prepared to receive the filteredmixture from recovery tank 144. A vacuum cycle nitrogen purge isperformed on extraction tank 136 prior to filtration. Approximately10-15 pounds of celite is added to the mixture in recovery tank 144.Next, the mixture is filtered by opening valve 148, turning on pump 149,and allowing the mixture to flow through filter 220 situated alongpassage 147 and through passage 204 and open valve 205 to recycle intorecovery tank 144. Filter 220, in its preferred embodiment, is an18-inch, 12-tray Niagara filter preheated with atmospheric steam. Thereaction mixture is recycled through filter 220 and recovery tank 144until a clear filtrate is established. Throughout the filtrationprocess, recovery tank 144 is maintained at a temperature ofapproximately 45° C., and atmospheric steam is periodically charged intothe jacket (not shown) of filter 220. If the filtration takes longerthan one hour, filter 220 is blown with nitrogen and replaced. After thefiltrate becomes clear, valve 205 is closed and valve 185 opened so thatthe mixture is transferred from recovery tank 144 to extraction tank 136through passage 147. Throughout the transfer, the temperature ofextraction tank 136 is maintained at approximately 45° C. To ensure thatall product has been transferred from recovery tank 144 to extractiontank 136, the filter is blown with nitrogen through to extraction tank136.

Once the transfer to extraction tank 136 is complete, the reactionmixture is checked to ensure that the filtration was satisfactory. Ifnot satisfactory, the reaction mixture is pumped back to recovery tank144 and refiltered. Next, the temperature of the reaction tank is cooledto about 35° C. After the temperature adjustment, the batch is seededwith seed crystals of HMB. Subsequent to the seeding, the temperature isfurther cooled to about 30° C. over two hours, as the product beginsprecipitating, forming a milky white slurry. The reaction mixture isfurther cooled slowly to about 20-25° C. over four additional hours. Inthe final cooling step, the temperature of the reaction mixture iscooled slowly to about 0-5° C. over two hours and maintained at 5° C. orless for an additional hour.

In preparation for the finishing steps, centrifuge 210 is fully purgedwith nitrogen through nitrogen inlet 211, and a dedicated tote bag 212is mounted on drop chute 222. The ethanol wash tank 223 is prepared at atemperature of about 0-5° C. for each batch wash. Ethanol is added toeach centrifuge load through passage 209. The filtrate is directed tothe filtrate tank 225 where it is periodically checked for solids beforebeing sent to the used ethanol drums for disposal.

The batch is centrifuged, generally in several loads, with each tote bagreceiving one centrifuge load. Once the entire batch has beencentrifuged, the batch is charged into dryer 213 and dried forapproximately 4 hours before sampling. When the sample shows a loss ondrying of about 0.1% or less, dryer 213 is unloaded to blender 214 andthen through screen 215, preferably a 600-micron screen, to delump thematerial. The resulting product from one batch according to thisprocedure will yield 30 or more pounds of finished HMB, more typically50 or more pounds, more typically 100 or more pounds, more typically 200or more pounds, more typically 300 or more pounds, more typically 400 ormore pounds, with an average amount of HMB of approximately 421 pounds.Based on the amount of DIA used, the yield is generally 0.330 or morepounds of HMB per pound of DIA charged, more typically 0.35 or morepounds of HMB per pound of DIA charged, more typically 0.4 or morepounds of HMB per pound of DIA charged, with an average yield of 0.44pounds of HMB per pound of DIA charged. The final material is drummed asone lot into 30-gallon leverpaks with plastic liners and labeled as HMBfinished. A sample of the finished product is provided to thelaboratory.

EXAMPLE

A. Conducting the Reaction

To begin the procedure, the auxiliary chiller, chiller pump, andassociated generator were turned on approximately 275 minutes prior tothe charging of bleach into the reactor. The methanol/water solutionexhibited a specific gravity of 0.935. After the cooling solutionexhibited a temperature of 18° F. (−10° C.) or less at the chiller inlettemperature probe, 1,200 gallons of 12.5-15% (pH 12.0-13.5) sodiumhypochlorite was charged into the reactor to begin the reactionprocedure.

The agitator and the recycling cooling loop pump were turned on, and thetemperature of the sodium hypochlorite was lowered to 0-5° C. After thetarget temperature for the sodium hypochlorite was reached, 957 poundsof diacetone alcohol was added at a rate of 1.3-2.9 pounds per minute.After DIA addition was completed, the DIA line was flushed withapproximately 5 gallons of de-ionized water. The temperature of thereactor was then maintained at 3-10° C. for 30 minutes.

After 30 minutes, approximately 2,120 pounds of 32% hydrochloric acidwas added to the reaction mixture. The acid was added at a rate ofapproximately 50-100 pounds per minute. At the completion of the acidaddition, the reaction mixture was maintained for 30 minutes at 10-20°C. while the pH was adjusted to 3.0-3.2 by adding approximately 510pounds of 32% hydrochloric acid. Again, the acid was added at a rate ofabout 50-100 pounds per minute. The reaction mixture was then agitatedfor 10 minutes, after which the pH was determined to be 3.20.

After approximately 20 minutes, the auxiliary chiller was shut down,while the cooling solution recirculating pump remained on for anadditional 10 minutes. Subsequently, the cooling solution pump and thereaction mixture recycling pump were shut down. The reactor bottom valvewas closed and the reaction mixture recycling cooling loop was flushedwith water and then with a nitrogen blow. Next, the cooling solutionflow to the reactor jacket was shut down and blown. The reactor agitatorwas shut off and the reaction mixture was allowed to settle forapproximately 20 minutes. The chloroform layer which formed on thebottom of the reactor was drained through the reactor bottom valve,generating approximately 848 pounds of chloroform waste stored in 2drums, to both of which 4 ounces of soda ash and 4 ounces of ethanolwere added.

B. Isolating the HMB Crude Product

(1) Water Strip

The next step in the process involved stripping water from the reactor.First, a full vacuum was pulled on the reactor container to 26-27 inchesof water (less than 200 mmHg). The reactor was heated with agitation toa distillation temperature of less than 70° C. Approximately 15 gallonsof water was distilled to a glass receiver, drummed out, and labeled. Atotal of approximately 750 gallons was distilled from the reactor to a600-gallon stainless steel water strip holding tank, 250 gallons ofwhich was drummed out into a tote bin.

After the water strip was completed and shut down, the contents of thereactor were cooled to approximately 25° C. using agitation and thecooling jacket. Next, approximately 270 pounds of 32% hydrochloric acidwas added through the top of the reactor to adjust the pH to 3.18. Theproduct mixture was agitated for 10 minutes and no additionalhydrochloric acid was necessary for addition since the pH had remainedat 3.18.

(2) Product Extraction

The next step in the process involved extracting the product from theaqueous salt slurry with ethyl acetate. After the agitator was shut off,the decant tube was lowered to the level of the liquid, approximately 77inches, and a mark was made in relation to the decant tube so that thedecant tube could be returned to the same position once the product hadbeen extracted into the ethyl acetate. The reactor was purged withnitrogen to an oxygen level of 8% or less. Approximately 500 gallons ofethyl acetate was added to the reactor from a 2,500-gallon stainlesssteel ethyl acetate recovery tank or from drums. The decant tube wasraised to the fall up position and the agitator was turned on for 30minutes. After 30 minutes, the agitator was turned off and the contentsof the reactor were allowed to settle for 20 minutes. The decant tubewas then lowered the 77 inches to the interface between the organic andaqueous layers. The upper ethyl acetate layer was then decanted to the2,000-gallon stainless steel ethyl acetate extraction tank.

The ethyl acetate extraction was performed two more times. In the lattertwo extractions, after the 30-minute agitation step, 32% hydrochloricacid was added to adjust the pH to the 3.0-3.2 range. In the secondextraction, in which 500 gallons of ethyl acetate was added, the pH wasadjusted to 3.2 by adding 50 pounds of hydrochloric acid. In the thirdextraction, in which 400 gallons of ethyl acetate was added, the pH wasadjusted to 3.10 by adding 15 pounds of hydrochloric acid. After each ofthe three extractions, a quart sample was collected and labeled with thebatch number and extraction number. After the third extraction, a cleancut was made because the third extraction was the final decant.

(3) Salt Layer Removal

After the three extractions were performed, the reactor contained saltwaste. The water distilled from the reactor in the earlier water stripstep was added back to the reactor from the water strip holding tank andthe tote bin in order to redissolve the salt waste remaining in thereactor. The mixture of the water and the salt waste was heated to about60° C. under vacuum to remove residual organics, and the contents werethen cooled to 25° C. The waste salt solution was pumped to a9,500-gallon stainless steel waste tank, and a 4-ounce sample wascollected during the transfer.

(4) Ethyl Acetate Recovery and HMB Crude Isolation

Approximately 1,400 gallons of ethyl acetate containing the product wasaccumulated in the ethyl acetate extraction tank. Approximately 10-20pounds of water which had been inadvertently transferred during thedecanting steps was drained from the bottom of the ethyl acetateextraction tank. Next, a mild vacuum of 12-15 inches of mercury waspulled on the extraction tank and recovery tank system. The extractiontank was heated with mild steam not exceeding a temperature in theextraction tank of 70° C. The vacuum and heat caused distillation ofethyl acetate into the recovery tank. The residue remaining in theextraction tank after the distillation was approximately 1,508 pounds ofHMB crude oil. The HMB crude oil was thereafter transferred to a producttote bin from the extraction tank, and a 4-ounce sample was collectedand labeled.

C. Finished HMB Preparation

The extraction tank was inspected for general cleanliness. Five batchesof HMB crude oil, a total of 6,398 pounds, generated as in the exampleabove were charged into the reactor from tote bins through a 10μ bagfilter to remove small amounts of residual salt. Next, the best possiblevacuum was pulled on the reactor to distill the residual ethyl acetateinto the water strip holding tank. The temperature of the reactor wasmaintained at less than 60° C., and in this case, at the start of thedistillation, the temperature was 22° C. and the vacuum was 26 inches ofmercury (100 mm of vacuum), while the temperature at the end of thedistillation was 56° C. and the vacuum was 26 inches. A nitrogen spargewas conducted next, beginning at 56° C. and 26 inches. The HMB crude oilwas transferred to two clean tote bins, providing a net weight of 2,491pounds. Two 5-gallon pails of the HMB crude oil was also collected foruse later in the procedure. Eight drums of ethyl acetate were drummedoff from the water strip holding tank.

The HMB crude oil earlier transferred to tote bins for weighing wasrecharged into the reactor. Recovery tank 144 was washed and thencleaned with several vacuum cycles and with jacket steam to eliminateethyl acetate odor. Twenty-one drums (approximately 7,560 pounds) ofethanol SD3A was charged into recovery tank. The HMB crude oil was thentransferred from the reactor to the recovery tank through a 10μ bagfilter.

Next, the recovery tank agitator was used to stir the ethanol/HMB crudeoil mixture while it was heated to 20° C. The following step comprisedadding 66 gallons of de-ionized water to the recovery tank. Thereafter,622 pounds of calcium hydroxide USP was added to the recovery tank at acontrolled rate, keeping the temperature of the contents between 30° C.and 45° C., and adjusting the final pH to 6.73. The HMB crude saved fromearlier in the process was not used to adjust the pH because the targetrange (6.5-7.0) was achieved without overshooting. Once the pHadjustment was completed, the recovery tank was fully purged withnitrogen and the temperature was maintained at between 30-45° C. Thetemperature was then maintained at 50° C. for one hour. Next,approximately 26 pounds of celite was added to the recovery tank, andthe contents were agitated for 10 minutes.

The extraction tank was set up to receive filtered solution from therecovery tank by performing a vacuum cycle nitrogen purge, making sureno ethyl acetate odor remained in the extraction tank. The jacketed18-inch, 12-tray, stainless steel filter with filter pads was prepared,ensuring that the filter was changed prior to processing the currentbatch. Before filtering, three drums (approximately 1,080 pounds) ofethanol was added to the reaction mixture.

The mixture was filtered at 50° C. from the recovery tank to theextraction tank until a sample from the loop demonstrated a clearfiltrate. Once the transfer to the extraction tank was completed, thetemperature of the contents of the tank was adjusted to 35° C. and 28pounds of seed crystals were added. Subsequent to the seeding, thetemperature was maintained at 35° C. for two hours. At approximately 33°C., the contents of the tank began to turn milky. Next, the extractiontank was cooled slowly to 20° C. over one hour and maintained at 20° C.for an additional hour. In the final cooling step, the temperature ofthe extraction tank was cooled slowly to 5° C. over two hours andmaintained at 5° C. for an additional hour.

The batch was then centrifuged in ten loads at 600 rpm, washing eachload with approximately 100 gallons of ethanol. The filtrate containingthe HMB product was directed to the filtrate tank where it wasperiodically checked for solids before being sent to the used ethanoldrums for disposal. Once the entire batch had been centrifuged, thebatch was charged into the dryer and dried at full flow for 24 hours at45-50° C. before sampling. The first dryer sample showed an LOD of 0.1%or less. The dryer was then unloaded to the blender and then to thescreener to delump the material. The final material was drummed as onelot into 30-gallon leverpaks with plastic liners for a total net weightof 2,200 pounds.

Thus, while the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiment,it is to be understood that the invention is not to be limited to thedisclosed embodiment, but on the contrary, is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

What is claimed is:
 1. In a large scale reaction, a process formanufacturing 3-hydroxy-3-methylbutanoic acid or a salt thereof,comprising the steps of: providing a large scale reaction systemcomprising a reactor, a first temperature probe therein, and anassociated recycle cooling loop comprising an outlet passage in fluidcommunication with the reactor, an external heat exchanger connected tothe outlet passage, and an inlet passage connected to the external heatexchanger and the reactor, wherein a second temperature probe isprovided on the outlet passage, and wherein a reactant solution can flowfrom the reactor through the outlet passage to the heat exchanger andthen through the inlet passage to the reactor; charging the reactionsystem with a solution of oxidant; cooling the solution of oxidant to atemperature below 15° C. by pumping the solution of oxidant through theexternal heat exchanger; feeding into the reaction system a large scaleamount of 4-hydroxy-4-methyl-2-pentanone; and recovering3-hydroxy-3-methylbutanoic acid or a salt thereof in yield of 0.33 ormore pounds HMB per pound of 4-hydroxy-4-methyl-2-pentanone.
 2. Theprocess of claim 1, wherein the solution of oxidant is cooled to andmaintained at a temperature below 10° C.
 3. The process of claim 2,wherein the step of feeding into the reaction system a large scaleamount of 4-hydroxy-4-methyl-2-pentanone includes the step of feeding4-hydroxy-4-methyl-2-pentanone into the outlet passage of the reactionsystem.
 4. The process of claim 2, further comprising the step ofcharging the reaction system with acid.
 5. The process of claim 4,wherein the step of charging the reaction system with acid includescharging the reactor with hydrochloric acid and adjusting the pH toapproximately 3.5 or lower.
 6. The process of claim 2, furthercomprising the steps of: extracting 3-hydroxy-3-methylbutanoic acid withan organic solvent; and concentrating 3-hydroxy-3-methylbutanoic acid byvacuum distillation.
 7. The process of claim 6, wherein the organicsolvent is ethyl acetate.
 8. The process of claim 2, wherein thereaction system further comprises a third temperature probe on the inletpassage and beyond the external heat exchanger.
 9. The process of claim2, wherein the external heat exchanger is a carbate heat exchanger. 10.The process of claim 2, wherein the external heat exchanger furtherincludes a cooling tank holding a cooling fluid, a cooling inletpassage, and a cooling outlet passage, all in fluid communication withthe external heat exchanger.
 11. The process of claim 10, wherein thecooling fluid is a solution of methanol and water, and wherein thecooling tank is maintained at a temperature of lower than −10° C. 12.The process of claim 11, wherein the cooling tank is maintained at atemperature of lower than −20° C.
 13. The process of claim 10, whereinthe external heat exchanger further includes a fourth temperature probeon the cooling inlet passage and a fifth temperature probe on thecooling outlet passage.
 14. The process of claim 2, wherein the reactorhas a capacity of at least one thousand gallons.
 15. The process ofclaim 2, wherein the step of cooling the solution of oxidant includesthe step of pumping the solution of oxidant through the external heatexchanger at a rate of at least 80 gallons/min.
 16. The process of claim2, wherein the step of feeding into the reaction system a large scaleamount of 4-hydroxy-4-methyl-2-pentanone includes the step of adjustingthe rate of addition of 4-hydroxy-4-methyl-2-pentanone based ontemperature readings at the first and second temperature probes.
 17. Theprocess of claim 6, wherein the reactor further includes an adjustabledecant tube to facilitate rapid extraction with organic solvent.
 18. Theprocess of claim 2, wherein a total of 100 pounds or more of4-hydroxy-4-methyl-2-pentanone is fed into the reaction system.
 19. Theprocess of claim 1, wherein the oxidant is selected from the groupconsisting of hypochlorite and hypobromite.
 20. The process of claim 1,wherein the step of feeding into the reaction system a large scaleamount of 4-hydroxy-4-methyl-2-pentanone is performed while maintainingthe solution of 4-hydroxy-4-methyl-2-pentanone and oxidant at atemperature below 15° C.
 21. In a large scale reaction, a process formanufacturing 3-hydroxy-3-methylbutanoic acid or a salt thereof,comprising the steps of: providing a large scale reaction system havingan adjustable decant tube associated with an internal portion thereof;charging the reaction system with a solution of oxidant; cooling thesolution of oxidant to a temperature below 15° C. by use of a heatexchanger; feeding into the reaction system a large scale amount of4-hydroxy-4-methyl-2-pentanone; and extracting3-hydroxy-3-methylbutanoic acid with an organic solvent, wherein theadjustable decant tube facilitates rapid extraction of the organicsolvent with clean cuts.
 22. The process of claim 21, further comprisingthe step of charging the reaction system with acid to produce3-hydroxy-3-methylbutanoic acid.
 23. The process of claim 21, whereinthe oxidant is selected from the group consisting of hypochlorite,hypobromite, and hypoiodite.
 24. The process of claim 21, wherein thestep of feeding into the reaction system a large scale amount of4-hydroxy-4-methyl-2-pentanone is performed while maintaining thesolution of 4-hydroxy-4-methyl-2-pentanone and oxidant at a temperaturebelow 15° C.